A series of new synthetic nucleoside analogs modified by attachment of a long hydrocarbon chain at the 3'-position of the sugar moiety will be evaluated in respect to membrane transport, intracellular phosphorylation to the nucleotide level, and resistance to adenosine deaminase cleavage. It is hoped that, upon metabolic conversion to nucleotides, these lipophilic nucleoside analogs will interfere with transcription and post-transcriptional RNA processing and/or DNA transcription. Biochemical studies will include experiments on the competitive transport of (3H)-adenosine, the extent of formation of mono-, di-, and tri-(32P)-phosphate esters, and the kinetics of enzymatic deamination. Effects of macromolecular synthesis will be studied via measurement of (3H)-uridine incorporation into RNA, (3H)-thymidine incorporation into DNA, and (3H)-leucine incorporation into protein. One lipophilic nucleoside analog already synthesized in this laboratory has shown a marked ability to inhibit both RNA and DNA biosynthesis in human lymphoblastic leukemia cells (CCRF-CEM) in culture. Preliminary studies show that this compound has a Km value for calf intestinal adenosine deaminase which is ten times higher than the Km value of cordycepin, and that it is cleaved at a substantially slower rate than cordycepin on incubation with a sonicated extract from CCRF-CEM cells. The aim of the proposed research is to elucidate the mechanism of action of this compound, to define the structure-activity requirements for optimal effect on cell growth, and to explore the potential usefulness of this and similar nucleosides as experimental cancer chemotherapeutic agents.